The selective loss of neurons is a hallmark of Alzheimer's disease (AD). However, imaging and biochemical studies now indicate that AD is also a demyelinating disease, characterized by white matter damage and decreases in myelin proteins apparent early in the disease that contribute to loss of cognitive function (1-5). It is critical to identify molecules that impact these white matter deficits to reverse consequences of the AD. This supplement is designed to address this issue, It uses information obtained in the parent grant that addresses a central question in demyelinating diseases such as MS: how can we prevent demyelination and enhance remyelination after a demyelinating lesion? Our work reveals that in the cuprizone demyelinated model, brain-derived neurotrophic factor (BDNF) reverses declines in myelin proteins. Moreover, it can be stimulated to do so by metabotropic glutamate receptor agonists. Effects of mGluR agonists are associated with enhanced production of astrocyte (AST)-derived BDNF and metabotropic glutamate receptors on ASTs. Our recent results show that these effects are mimicked by CHPG, a mGluR5 specific agonist that is administered either stereotaxically or peripherally, suggesting its effects may be important therapeutically. In this supplement, we test whether effects of CHPG may be useful in reversing white matter deficits in AD. To approach this issue we have begun to evaluate effects of BDNF and CHPG in the triple transgenic AD mouse model (3xTg-AD; 6) that, as in AD, exhibits myelin disruption (7). We focused our attention on the basal forebrain (BF), a region that degenerates in AD (8-10) and that we found in previous work is impacted by a reduction in BDNF by exhibiting reduced levels of myelin proteins (11). In preliminary work we found at 12 months of age that the BF exhibits a reduction in BDNF that is correlated with a loss in myelin proteins. Importantly, this loss in myelinated proteins is reversed by an injection of BDNF into the lateral ventricle. To determine if the reduction in BDNF is affected by CHPG, our most recent studies have injected the drug peripherally as we do in the cuprizone model. CHPG (3X/wk) reverses decreases in BDNF and myelin proteins in the 3xTg-AD model after i.p. injections over a week, suggesting that it may be effective in AD. We hypothesize that it works through the same mechanism as observed in MS models. CHPG elicits increases in AST-derived BDNF that stimulates OLGs to differentiate and myelinate. To test this possibility in pilot studies of one year we will determine 1) if increases in myelin proteins elicited by CHPG are associated with increases in myelin in multiple brain regions and 2) begin to identify the role of AST-derived BDNF in reversing deficits in myelin such as occur in AD. We hypothesize that CHPG may be valuable in reversing myelin deficits in AD where degenerative changes in myelin may contribute to cognitive deficits.